Recent research in the fields of separation technology and pharmaceutical compounds reveals that many reactions between chemical compounds result from the three dimensional structure, and the molecular interactions between different compounds. A complementary structural relationship has been tied to a particular chemical compounds ability to react with a second chemical compound (see, for example, "The Concept of Molecular Structure in Structure-Activity Relationship Studies and Drug Design", Testa et al., Medicinal Research Reviews, 1991, Vol. 11, No. 1). The present invention relates to hydroxyethyl aminimide chemical structures which can be used as molecular scaffolding on which to hang different substituent groups. By varying the different substituent groups on an aminimide chemical backbone as disclosed herein it is possible to develop chemical compounds having a complementary structural and molecular relationship to a target compound, enzyme, molecular recognition site or receptor. Use of the present invention represents an improvement in both the cost and time efficiency of identifying lead compounds.
Hydroxyethyl aminimides (herein after referred to as aminimides), can be prepared from the one-step reaction of an ester or acid chloride, a hydrazine, and an epoxide according to a method such as that disclosed by Middleton, U.S. Pat. No. 3,963,776 and Culbertson, U.S. Pat. No. 3,963,703. Alternatively, hydroxyethyl aminimides can be formed from the alkylation of a disubstituted hydrazide through the opening of an epoxide such as by the reactions disclosed in Grimm, U.S. Pat. No. 3,850,969. An extensive discussion of aminimides including their preparation and uses is set forth in PCT application PCT/US93/12612 filed Dec. 28, 1993 in the name of ArQule Partners, L.P., which is herein incorporated by reference in its entirety.
Aminimides have a diversity of properties, and are known to be useful as surfactants, (see, for example, Falk, U.S. Pat. No. 4,102,916, and Middleton, U.S. Pat. No. 3,963,776), resin hardeners, precursors to isocyanates (see, for example, Brutchen, U.S. Pat. No. 3,898,087), in the formation of polyurethanes (see, for example, Kresta, U.S. Pat. No. 4,067,830) and polyisocyanurates (see Kresta, U.S. Pat. No. 3,925,284).
Much less is known about the biological activity of aminimides. Kabara has shown that specific aliphatic derived dimethyl-hydroxyethyl aminimides possess antimicrobial (see U.S. Pat. Nos. 4,189,481 and 4,217,364) and antifungal properties (see U.S. Pat. Nos. 3,934,029 and 3,934,031). L. Boutis, et al., have observed antineoplastic activity (Current Chemotherapy, 1978, 2, 1213-1216), while M. Tichniouin, et al. demonstrated that certain dimethyl-hydroxyethyl aminimides possess a noticeable vasodilating activity (Eur. J. Med. Chem., 1982, 17, 265-270). Yet, to date, no one has used an aminimide moiety, and, in particular, a hydroxyethyl aminimide moiety as a peptide isostere in the design of pharmacologically active compounds.
The present invention relates to the use of hydroxyethyl aminimides as isosteres in the design and synthesis of chemical compounds capable of binding to an active site of a receptor or enzyme or to a molecular recognition site in, for example, separation chemistry.